ADA 2023 – Toxicity undermines Boehringer and Zealand’s incretin

A quarter of patients fail to stomach survodutide.

Data presented late yesterday appears to suggest once again that the only thing glucagon agonism adds to GLP-1 agonism is toxicity. The side effects of survodutide, the GLP-1/glucagon co-agonist being developed by Boehringer Ingelheim and Zealand Pharma, prompted high levels of discontinuation in a mid-stage obesity trial. 

In this survodutide is following the example set by Altimmune’s pemvidutide, which prompted almost identical levels of dropouts in its own phase 2 obesity study. With neither of these products distinguishing themselves from the efficacy shown by Novo Nordisk’s GLP-1 Wegovy, still the only incretin approved for obesity, the future of this class is starting to look uncertain. 

The phase 2 trial of survodutide, formerly called BI 456906, was toplined last month, but no safety data were released. The full results, presented at the American Diabetes Association’s annual meeting yesterday evening, confirm that survodutide’s efficacy at 46 weeks looks roughly on a par with Wegovy’s, if somewhat behind that of Lilly’s Mounjaro, which has a different mechanism to either. 

Obesity cross-trial comparison 
Company Novo Nordisk Lilly Boehringer Ingelheim/Zealand
Trial Step 1 (Ph3, NCT03548935) Surmount-1 (Ph3, NCT04184622) Ph2, NCT04667377
Project and dose Wegovy 2.4mg Mounjaro 15mg (high dose) Survodutide 3.6mg Survodutide 4.8mg
Mechanism GLP-1 analogue GIP/GLP-1 agonist GLP-1/glucagon agonist 
Pbo-adj weight loss at 46wk (%) ~12 ~18 10.4 12.1
Safety (all pbo-adj)
Nausea (%) 26.8 21.5 42.8 44.1
Diarrhoea (%) 15.6 15.7 13.0 9.1
Vomiting (%) 18.2 10.5 28.6 29.9
Constipation (%) 13.9 5.9 19.5 20.8
Discontinuations due to adverse events (%) 3.9 3.6 20.8 24.7
Mounjaro efficacy data are efficacy estimands. Survodutide data are for the highest two doses only, and from the ITT analysis. AE data at 68wks for Wegovy, 72wks for Mounjaro and 46wks for survodutide. Source: company releases, NEJM, ADA abstract 51-OR.

It is the adverse event rates, and particularly AE-related discontinuations, that stand out. Nearly a quarter of patients on the highest dose of survodutide backed out of the trial citing side effects. This has strong echoes of the dropouts seen with Altimmune’s pemvidutide in its obesity study, though that cut was only at 24 weeks. 

Intriguingly pemvidutide looked rather safer in Nash, according to data released this week at the Easl meeting. 

Turn on, tune in

“My old professor of pharmacology used to say there’s only two types of drugs – drugs that don’t work and drugs that have side effects,” said Carel le Roux of University College Dublin, presenting the results at ADA. “And this is no different.”

He said that “many, if not most” of the events had occurred in the 20 week dose titration stage of the trial, and suggested that while weight loss with survodutide would deepen further over time, safety could be improved with slower titration. 

This might be true. But Boehringer and Zealand had hoped survodutide would escape this level of toxicity since it has eightfold greater affinity for the GLP-1 receptor than the glucagon receptor. Pemvidutide is equimolar.

The results seen in obesity with survodutide and pemvidutide suggest that GLP-1/glucagon agonists are only roughly as effective as Wegovy (and less effective than Mounjaro), but much less safe.  

Many other groups are also working on this mechanism, in obesity, diabetes or NAFLD/Nash. Some appear to be safer than survodutide and pemvidutide, with Innovent and Lilly’s mazdutide doing particularly well: the only AE-related withdrawals in its China-based phase 2 obesity trial occurred in the placebo group.

Still, larger phase 3 trials are underway with that project and Astrazeneca’s cotadutide, and larger patient numbers should give greater insight into both efficacy and safety. Recent developments must surely give developers of GLP-1/glucagon agonists, and their investors, reason to be wary. 

Selected GLP-1/glucagon agonists in development for obesity and other metabolic disorders
Project Company Status
Phase 3
Cotadutide Astrazeneca Ph2a trial in T2D with chronic kidney disease showed improved glucose control and reduced bodyweight, with 9.5% AE-related discontinuations.
Ph2/3 Nash trial could report 2024.
Mazdutide (IBI362/OXM3) Innovent/Lilly Ph2 obesity trial showed up to 15.4% pbo-adj weight loss in obesity, and 0% AE-related discontinuations. 
Ph3 obesity trial and two Ph3 T2D trials could report 2024.
Phase 2
(BI 456906)
Boehringer Ingelheim/
Zealand Pharma
Ph2 obesity trial showed up to 12.1% pbo-adj weight loss in obesity, but 25% AE-related discontinuations. 
Ph2 Nash trial could report 2024.
Pemvidutide Altimmune Ph2 obesity trial showed up to 9.7% pbo-adj weight loss in obesity, but 24% AE-related discontinuations.
Ph1 NAFLD trial showed liver fat reductions, with 6% AE-related discontinuations.
Ph2 Nash trial planned.
Efinopegdutide (HM12525A) Merck/Hanmi Ph2 NAFLD trial showed liver fat reductions vs semaglutide, with 6% AE-related discontinuations.
Source: Evaluate Pharma, & company websites.

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